The goal of this research is to assess the safety of commonly used medications in relation to the risk of incident atrial fibrillation (AF), and to assess the association of several genetic polymorphisms with stroke risk after AF onset. Several lines of evidence suggest that both beta-blockers and ACE inhibitors may prevent or inhibit the atrial electrical remodeling that allows AF to become established and maintained. Withdrawal of these medications may be associated with increased risk of AF in individuals at risk. Genetic polymorphisms that promote thrombosis are associated with an increased risk of venous thrombosis, and in some studies, with arterial thrombosis including stroke or myocardial infarction. Although several recently published trials indicate that warfarin or aspirin treatment of patients with AF decreases the risk of stroke, little is known about the risk of stroke as a complication of AF in relation to genetic variants that affect clotting. The proposed project will build on successful population-based studies of myocardial infarction and stroke at Group Health Cooperative (GHC), a large non-profit health maintenance organization. Detailed information from the GHC computerized pharmacy database on the timing of medication use among approximately 1500 incident AF cases and 1750 controls with medically treated hypertension will permit us to assess the risk of incident AF associated with the use or recent stopping of beta-blockers or ACE inhibitors. This project will collect DNA samples on a population-based inception cohort of approximately 855 AF patients, and will examine the risk of stroke in relation to genetic variants known to affect coagulation. The main tasks of the proposed project are: 1) identification of cases with incident AF and controls; 2) review of outpatient and inpatient medical records to assess eligibility and collect information on risk factors and medical history; 3) classification of medication use over time; 4) for AF patients, telephone interview and collection of blood samples; 5) blood specimen processing, DNA extraction, and genotyping; and 6) data analysis of the associations of medication use and genotype with AF onset and stroke complications. This project will contribute important information about drug safety and will incorporate advances in molecular biology to study AF and its complications, problems of considerable public health importance in the elderly.